: Most symptoms of Parkinson's Disease (PD) are thought to occur as a result of loss of the nigrostriatal dopaminergic pathway. However, it is now evident that for many PD patients failure of response to antiparkinsonian medication is linked to spreading of pathology to other dopamine (DA) systems, and, possibly to changes in expression of postsynaptic DA receptors. It has been proposed that rigidity, tremor and secondary akinesia start first with degeneration of the nigrostriatal DA system followed by spread of the pathology to the mesolimbic DA system, which may produce primary akinesia, dementia and depression. This spreading of pathology from one functional system to another might be one of the key factors responsible for the progressive worsening of the motoric symptoms and increase in non-responders with disease duration. However, research on changes in postsynaptically located DA receptors has focused on contributions of the D2 receptor to changes in Parkinsonian symptoms, and it has been specifically hypothesized that loss of responsiveness in late-stage PD results from reduced D2 receptor number. Our evidence shows that another member of the D2 receptor family, the D3 receptor, which is a target receptor for the mesolimbic DA system, plays a predominant role in the deteriorated response of L-dopa and DA agonists in advanced PD. We will test if disease related changes in the postsynaptic (loss of D3 receptor), as well as presynaptic, components of the mesolimbic DA system contribute to the loss of effective response of antiparkinsonian medication in PD patients, and to the presence of dementia. The present research is therefore focused on postmortem studies that provide: (1) identification of changes in D3 receptor expression in subgroups of PD; (2) identifying changes in the expression of D3 receptor mRNA relative to D, and D2 receptor mRNAs in striatal-pallidal-thalmo pathways; (3) relationship of changes in D3 receptor expression and clinical symptoms to loss of mesolimbic DA system; and (4) use of experimental models of PD to study regulation of the D3 receptor, and identify why antiparkinsonian medication eventually fails to upregulate this receptor. This will further elucidate the pathology of DAergic substrates of specific clinical symptoms in PD and provide a broader basis for developing effective treatment strategies based on specific DA receptors.